US7642229B2 - Pharmaceutical composition and a product which includes a substituted acryloyl distamycin derivative, an antimicrotubule agent and/or an antimetabolite - Google Patents

Pharmaceutical composition and a product which includes a substituted acryloyl distamycin derivative, an antimicrotubule agent and/or an antimetabolite Download PDF

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US7642229B2
US7642229B2 US10/297,620 US29762002A US7642229B2 US 7642229 B2 US7642229 B2 US 7642229B2 US 29762002 A US29762002 A US 29762002A US 7642229 B2 US7642229 B2 US 7642229B2
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amino
methyl
pyrrol
carbonyl
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Maria Cristina Rosa Geroni
Paolo Cozzi
Italo Beria
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Pfizer Italia SRL
Nerviano Medical Sciences SRL
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the field of cancer treatment and provides an antitumor composition
  • an antitumor composition comprising a substituted acryloyl distamycin derivative, more particularly an ⁇ -bromo- or ⁇ -chloro-acryloyl distamycin derivative, an antimicrotubule agent and/or an antimetabolite, having a synergistic antineoplastic effect.
  • Distamycin A and analogues thereof are known in the art as cytotoxic agents useful in antitumor therapy.
  • Distamycin A is an antibiotic substance with antiviral and antiprotozoal activity, having a polypyrrole framework [ Nature 203: 1064 (1964); J. Med. Chem. 32: 774-778 (1989)].
  • the international patent applications WO 90/11277, WO 98/04524, WO 98/21202, WO 99/50265, WO 99/50266 and WO 01/40181 (claiming priority from British patent application No.
  • the present invention provides, in a first aspect, a pharmaceutical composition for use in antineoplastic therapy in mammals, including humans, comprising a pharmaceutically acceptable carrier or excipient;
  • the present invention includes, within its scope, the pharmaceutical compositions comprising any of the possible isomers covered by the compounds of formula (I), both considered separately or in admixture, as well as the metabolites and the pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I).
  • distamycin or distamycin-like framework R 2 we intend any moiety structurally closely related to distamycin itself, for instance by optionally replacing the ending amidino moiety of distamycin and/or its polypyrrole framework, or part of it.
  • Antimicrotubule agents and antimetabolites are widely known in the art as antitumor agents; see, for a general reference, Cancer, Principles and Practice of Oncology, Lippincott-Raven Ed. (1997), 432-452 and 467-483
  • the antimicrotubule agents are, for instance, taxanes, e.g. paclitaxel or docetaxel; vinca alkaloids, e.g. vincristine, vinblastine, vindesine, vinorelbine; and estramustine, optionally encapsulated within liposomes.
  • taxanes e.g. paclitaxel or docetaxel
  • vinca alkaloids e.g. vincristine, vinblastine, vindesine, vinorelbine
  • estramustine optionally encapsulated within liposomes.
  • Preferred antimetabolites are, for instance, antifolates, e.g. metotrexate, trimetrexate, tomudex; 5-fluoropyrimidines, e.g. 5-FU, floxuridine, ftorafur and capecitabine; cytidine analogs, e.g. cytarabine, azacitidine and gemcitabine.
  • antifolates e.g. metotrexate, trimetrexate, tomudex
  • 5-fluoropyrimidines e.g. 5-FU, floxuridine, ftorafur and capecitabine
  • cytidine analogs e.g. cytarabine, azacitidine and gemcitabine.
  • antimicrotubule agents are paclitaxel and estramustine whereas preferred antimetabolites are 5-fluorouracil or gemcitabine.
  • Q is a nitrogen atom or a CH group and W is an oxygen or sulfur atom or it is a group NR 3 wherein R 3 is hydrogen or C 1 -C 4 alkyl;
  • C 1 -C 4 alkyl or alkoxy group we intend a straight or branched group selected from methyl ethyl, n-propyl isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, see-butoxy or tert-butoxy.
  • compositions of the invention comprising the above acryloyl distamycin derivative of formula (I) wherein R 1 is bromine or chlorine; R 2 is the above group of formula (II) wherein r is 0, m is 0 or 1, n is 4 and B has the above reported meanings.
  • compositions comprising the compounds of formula (I) wherein R 1 is bromine or chlorine; R 2 is the above group of formula (II) wherein r is 0, m is or 1, n is 4, X and Y are both CH groups and B is selected from:
  • Pharmaceutically acceptable salts of the compounds of formula (I) are those with pharmaceutically acceptable inorganic or organic acids such as, for instance, hydrochloric, hydrobromic, sulfuric, nitric, acetic, propionic, succinic, malonic, citric, tararic, methanesulfonic, p-toluenesulfonic acid and the like.
  • compositions object of the invention optionally in the form of pharmaceutically acceptable salts, preferably with hydrochloric acid, are:
  • the present invention further provides a product comprising an acryloyl distamycin derivative of formula (I), as defined above, an antimicrotubule agent and/or an antimetabolite, as a combined preparation for simultaneous, separate or sequential use in antitumor therapy.
  • a product comprising N-(5- ⁇ [(5- ⁇ [(5- ⁇ [(2-[amino(imino)methyl]amino ⁇ ethyl)amino]carbonyl ⁇ -1-methyl-1H-pyrrol-3-yl)amino]carbonyl ⁇ -1-methyl-1H-pyrrol-3-yl)amino]carbonyl ⁇ -1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride (internal code PNU 166196) and gemcitabine, as a combined preparation for simultaneous, separate or sequential use in antitumor therapy.
  • internal code PNU 166196 internal code
  • a further aspect of the present invention is to provide a method of treating a mammal, including humans, suffering from a neoplastic disease state, which method comprises administering to said mammal the above acryloyl distamycin derivative of formula (I), an antimicrotubule agent and/or an antimetabolite, in amounts effective to produce a synergistic antineoplastic effect.
  • the present invention also provides a method for lowering the side effects caused by antineoplastic therapy with an antineoplastic agent in a mammal in need thereof, including human, the method comprising administering to said mammal a combined preparation comprising an acryloyl distamycin derivative of formula (I), an antimicrotubule agent and/or an antimetabolite, in amounts effective to produce a synergistic antineoplastic effect.
  • antineoplastic effect it is meant the inhibition of the growth tumor, preferably the complete regression of the tumor, by administering an effective amount of the combination comprising an acryloyl distamycin derivative of formula (I), an antimicrotubule agent and/or an antimetabolite to mammals, including humans.
  • parenteral means intravenous, subcutaneous and intramuscular administration.
  • the acryloyl distamycin derivative may be administered simultaneously with the antimicrotubule agent or with the antimetabolite.
  • the two drugs maybe administered sequentially in either order.
  • the drugs are preferably administered sequentially, in any order.
  • the actual preferred method and order of administration will vary according to, inter alias, the particular formulation of the acryloyl distamycin of formula (I) being used, the particular formulation of the antimicrotubule agent and/or the antimetabolite being used, the particular tumor model being treated as well as the particular host being treated.
  • the course of therapy generally employed comprises doses varying from about 0.05 to about 100 mg/m 2 of body surface area and, more preferably, from about 0.1 to about 50 mg/m 2 of body surface area.
  • the course of therapy generally employed comprises doses varying from about 1 to about 1000 mg/m 2 of body surface area and, more preferably, from about 10 to about 500 mg/m 2 of body surface area.
  • the course of therapy generally employed comprises doses varying from about 0.1 to about 1000 mg/m 2 of body surface area and, more preferably, from about 0.5 to about 100 mg/m 2 of body surface area.
  • the course of therapy generally employed comprises doses varying from about 0.1 to about 10 g/m 2 of body surface area and, more preferably, from about 1 to about 5 g/m 2 of body surface area.
  • the antineoplastic therapy of the present invention is particularly suitable for treating breast, ovary, lung, colon, kidney, stomach, pancreas, liver, melanoma, leukemia and brain tumors in mammals, including humans.
  • the present invention is directed to a composition
  • a composition comprising an effective amount of an acryloyl distamycin derivative of formula (I), as defined above, an antimicrotubule agent and/or an antimetabolite, in the preparation of a medicament for use in the prevention or treatment of metastasis or in the treatment of tumors by inhibition of angiogenesis.
  • the effect of an acryloyl distamycin derivative of formula (I) with an antimicrotubule agent and/or an antimetabolite is significantly increased without a parallel increase of toxicity.
  • the combined therapy of the present invention enhances the antitumoral effects of the acryloyl distamycin derivative and of the other drug, being either an antimicrotubule, an antimetabolite or a combination thereof and, hence, provides the most effective and least toxic treatment for tumors.
  • Table 1 shows the antileukemic activity on disseminated L1210 murine leukemia obtained by combining N-(5- ⁇ [(5- ⁇ [(5- ⁇ [(2- ⁇ [amino(imino)methyl]amino ⁇ ethyl)amino]carbonyl ⁇ -1-methyl-1H-pyrrol-3-yl)amino]carbonyl ⁇ -1-methyl-1H-pyrrol-3-yl)amino]carbonyl ⁇ -1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride, as a representative compound of formula (I)—internal code PNU 166196, with gemcitabine.

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Abstract

A pharmaceutical composition and a product which includes an acryloyl distamycin derivative, an antimicrotubule agent and/or an antimetabolite useful in the treatment of tumors.

Description

REFERENCE TO RELATED APPLICATIONS
The present application is a national phase application, filed under 35 U.S.C. §371, based on PCT Application Serial No. PCT EP01/07060, filed Jun. 20, 2001.
The present invention relates to the field of cancer treatment and provides an antitumor composition comprising a substituted acryloyl distamycin derivative, more particularly an α-bromo- or α-chloro-acryloyl distamycin derivative, an antimicrotubule agent and/or an antimetabolite, having a synergistic antineoplastic effect.
Distamycin A and analogues thereof, hereinafter referred to as distamycin and distamycin-like derivatives, are known in the art as cytotoxic agents useful in antitumor therapy.
Distamycin A is an antibiotic substance with antiviral and antiprotozoal activity, having a polypyrrole framework [Nature 203: 1064 (1964); J. Med. Chem. 32: 774-778 (1989)]. The international patent applications WO 90/11277, WO 98/04524, WO 98/21202, WO 99/50265, WO 99/50266 and WO 01/40181 (claiming priority from British patent application No. 9928703.9), all in the name of the applicant itself and herewith incorporated by reference, disclose acryloyl distamycin derivatives wherein the amidino moiety of distamycin is optionally replaced by nitrogen-containing ending groups such as, for instance, cyanamidino, N-methylamidino, guanidino, carbamoyl, amidoxime, cyano and the like, and/or wherein the polypyrrole framework of distamycin, or part of it, is replaced by varying carbocyclic or heterocyclic moieties.
The present invention provides, in a first aspect, a pharmaceutical composition for use in antineoplastic therapy in mammals, including humans, comprising a pharmaceutically acceptable carrier or excipient;
    • an acryloyl distamycin derivative of formula (I):
Figure US07642229-20100105-C00001
      • wherein:
      • R1 is a bromine or chlorine atom;
      • R2 is a distamycin or distamycin-like framework; or a pharmaceutically acceptable salt thereof; and
    • an antimicrotubule agent and/or an antimetabolite.
The present invention includes, within its scope, the pharmaceutical compositions comprising any of the possible isomers covered by the compounds of formula (I), both considered separately or in admixture, as well as the metabolites and the pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I).
In the present description, unless otherwise specified, with the term distamycin or distamycin-like framework R2 we intend any moiety structurally closely related to distamycin itself, for instance by optionally replacing the ending amidino moiety of distamycin and/or its polypyrrole framework, or part of it.
Antimicrotubule agents and antimetabolites are widely known in the art as antitumor agents; see, for a general reference, Cancer, Principles and Practice of Oncology, Lippincott-Raven Ed. (1997), 432-452 and 467-483
According to a preferred embodiment of the invention, herewith provided are the above pharmaceutical compositions wherein the antimicrotubule agents are, for instance, taxanes, e.g. paclitaxel or docetaxel; vinca alkaloids, e.g. vincristine, vinblastine, vindesine, vinorelbine; and estramustine, optionally encapsulated within liposomes.
Preferred antimetabolites are, for instance, antifolates, e.g. metotrexate, trimetrexate, tomudex; 5-fluoropyrimidines, e.g. 5-FU, floxuridine, ftorafur and capecitabine; cytidine analogs, e.g. cytarabine, azacitidine and gemcitabine.
Particularly preferred antimicrotubule agents are paclitaxel and estramustine whereas preferred antimetabolites are 5-fluorouracil or gemcitabine.
According to another preferred embodiment of the invention, herewith provided are the above pharmaceutical compositions wherein, within the acryloyl distamycin derivative of formula (I), R1 has the above reported meanings and R2 is a group of formula (II) below:
Figure US07642229-20100105-C00002
wherein
  • m is an integer from 0 to 2;
  • n is an integer from 2 to 5;
  • r is 0 or 1;
  • X and Y are, the same or different and independently for each heterocyclic ring, a nitrogen atom or a CH group;
  • G is phenylene, a 5 or 6 membered saturated or unsaturated heterocyclic ring with from 1 to 3 heteroatoms selected among N, O or S, or it is a group of formula (III) below:
Figure US07642229-20100105-C00003
wherein Q is a nitrogen atom or a CH group and W is an oxygen or sulfur atom or it is a group NR3 wherein R3 is hydrogen or C1-C4 alkyl;
  • B is selected from the group consisting of
Figure US07642229-20100105-C00004
    • —CN; —NR5R6; —CONR5R6; —NHCONR5R6
      wherein R4 is cyano, amino, hydroxy or C1-C4 alkoxy; R5, R6 and R7, the same or different, are hydrogen or C1-C4 alkyl.
In the present description, unless otherwise specified, with the term C1-C4 alkyl or alkoxy group we intend a straight or branched group selected from methyl ethyl, n-propyl isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, see-butoxy or tert-butoxy.
Even more preferred are the pharmaceutical compositions of the invention comprising the above acryloyl distamycin derivative of formula (I) wherein R1 is bromine or chlorine; R2 is the above group of formula (II) wherein r is 0, m is 0 or 1, n is 4 and B has the above reported meanings.
Still more preferred, within this class, are the pharmaceutical compositions comprising the compounds of formula (I) wherein R1 is bromine or chlorine; R2 is the above group of formula (II) wherein r is 0, m is or 1, n is 4, X and Y are both CH groups and B is selected from:
Figure US07642229-20100105-C00005
    • —CN; —CONR5R6; —NHCONR5R6
      wherein R4 is cyano or hydroxy and R5, R6 and R7, the same or different, are hydrogen or C1-C4 alkyl.
Pharmaceutically acceptable salts of the compounds of formula (I) are those with pharmaceutically acceptable inorganic or organic acids such as, for instance, hydrochloric, hydrobromic, sulfuric, nitric, acetic, propionic, succinic, malonic, citric, tararic, methanesulfonic, p-toluenesulfonic acid and the like.
Examples of preferred acryloyl distamycin derivatives of formula (I), within the compositions object of the invention, optionally in the form of pharmaceutically acceptable salts, preferably with hydrochloric acid, are:
  • 1. N-(5-{[(5-{[(5-{[(2-{[amino(imino)methyl]amino}ethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride;
  • 2. N-(5-{[(5-{[(5-{[(2-{[amino(imino)methyl]amino}propyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride;
  • 3. N-(5-{[(5-{[(5-{[(3-amino-3-iminopropyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride;
  • 4. N-(5-{[(5-{[(5-{[(3-amino-3-iminopropyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-imidazole-2-carboxamide hydrochloride;
  • 5. N-(5-{[(5-{[(5-{[(3-amino-3-iminopropyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-3-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrazole-5-carboxamide hydrochloride;
  • 6. N-(5-{[(5-{[(5-{[(3-amino-3-oxopropyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-3-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrazole-5-carboxamide;
  • 7. N-(5-{[(5-{[(5-{[(2-{[amino(imino)methyl]amino}ethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-chloroacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride;
  • 8. N-(5-{[(5-{[(3-{[amino(imino)methyl]amino}propyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride;
  • 9. N-(5-{[(5-{[(3-amino-3-iminopropyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride; and
  • 10. N-{5-[({5-[({5-[({3-[(aminocarbonyl)amino]propyl}amino)carbonyl]-1-methyl-1H-pyrrol-3-yl}amino)carbonyl]-1-methyl-1H-pyrrol-3-yl}amino)carbonyl]-1-methyl-1H-pyrrol-3-yl}-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyyrole-2-carboxamide.
The above compounds of formula (I), either specifically identified as such or by means of the general formula, are known or easily prepared according to known methods as reported, for instance, in the aforementioned international patent applications WO 90/11277, WO 98/04524, WO 98/21202, WO 99/50265 and WO 99/50266 and WO 01/40181.
The present invention further provides a product comprising an acryloyl distamycin derivative of formula (I), as defined above, an antimicrotubule agent and/or an antimetabolite, as a combined preparation for simultaneous, separate or sequential use in antitumor therapy.
Particularly preferred, in this respect, is a product comprising N-(5-{[(5-{[(5-{[(2-[amino(imino)methyl]amino}ethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride (internal code PNU 166196) and gemcitabine, as a combined preparation for simultaneous, separate or sequential use in antitumor therapy.
A further aspect of the present invention is to provide a method of treating a mammal, including humans, suffering from a neoplastic disease state, which method comprises administering to said mammal the above acryloyl distamycin derivative of formula (I), an antimicrotubule agent and/or an antimetabolite, in amounts effective to produce a synergistic antineoplastic effect.
The present invention also provides a method for lowering the side effects caused by antineoplastic therapy with an antineoplastic agent in a mammal in need thereof, including human, the method comprising administering to said mammal a combined preparation comprising an acryloyl distamycin derivative of formula (I), an antimicrotubule agent and/or an antimetabolite, in amounts effective to produce a synergistic antineoplastic effect.
By the term “synergistic antineoplastic effect”, as used herein, it is meant the inhibition of the growth tumor, preferably the complete regression of the tumor, by administering an effective amount of the combination comprising an acryloyl distamycin derivative of formula (I), an antimicrotubule agent and/or an antimetabolite to mammals, including humans.
By the term “administered” or “administering”, as used herein, it is meant parenteral and/or oral administration; the term “parenteral” means intravenous, subcutaneous and intramuscular administration.
In the method of the present invention, the acryloyl distamycin derivative may be administered simultaneously with the antimicrotubule agent or with the antimetabolite. Alternatively, the two drugs maybe administered sequentially in either order.
When the acryloyl distamycin derivative is administered with both the antimicrotubule agent and the antimetabolite, according to an embodiment of the invention, the drugs are preferably administered sequentially, in any order.
In this respect, it will be appreciated that the actual preferred method and order of administration will vary according to, inter alias, the particular formulation of the acryloyl distamycin of formula (I) being used, the particular formulation of the antimicrotubule agent and/or the antimetabolite being used, the particular tumor model being treated as well as the particular host being treated.
To administer the acryloyl distamycin derivative of formula (I), according to the method of the invention, the course of therapy generally employed comprises doses varying from about 0.05 to about 100 mg/m2 of body surface area and, more preferably, from about 0.1 to about 50 mg/m2 of body surface area.
For the administration of the taxanes, according to the method of the invention, the course of therapy generally employed comprises doses varying from about 1 to about 1000 mg/m2 of body surface area and, more preferably, from about 10 to about 500 mg/m2 of body surface area.
For the administration of the vinca alkaloids, according to the method of the invention, the course of therapy generally employed comprises doses varying from about 0.1 to about 1000 mg/m2 of body surface area and, more preferably, from about 0.5 to about 100 mg/m2 of body surface area.
For the administration of the antimetabolite according to the invention, the course of therapy generally employed comprises doses varying from about 0.1 to about 10 g/m2 of body surface area and, more preferably, from about 1 to about 5 g/m2 of body surface area.
The antineoplastic therapy of the present invention is particularly suitable for treating breast, ovary, lung, colon, kidney, stomach, pancreas, liver, melanoma, leukemia and brain tumors in mammals, including humans.
In a further aspect, the present invention is directed to a composition comprising an effective amount of an acryloyl distamycin derivative of formula (I), as defined above, an antimicrotubule agent and/or an antimetabolite, in the preparation of a medicament for use in the prevention or treatment of metastasis or in the treatment of tumors by inhibition of angiogenesis.
As stated above, the effect of an acryloyl distamycin derivative of formula (I) with an antimicrotubule agent and/or an antimetabolite, is significantly increased without a parallel increase of toxicity. In other words, the combined therapy of the present invention enhances the antitumoral effects of the acryloyl distamycin derivative and of the other drug, being either an antimicrotubule, an antimetabolite or a combination thereof and, hence, provides the most effective and least toxic treatment for tumors.
The superadditive effects of the combined preparations of the invention are shown, for instance, by the following in vivo antitumor activity data which are intended to illustrate the present invention without posing any limitation to it.
Table 1 shows the antileukemic activity on disseminated L1210 murine leukemia obtained by combining N-(5-{[(5-{[(5-{[(2-{[amino(imino)methyl]amino}ethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride, as a representative compound of formula (I)—internal code PNU 166196, with gemcitabine.
At the dose of 15 mg/kg of gemcitabine alone (day +1 after tumor injection, 2 h after PNU 166196 administration) and at the dose of 0.7 mg/kg of PNU 166196 alone (days +1,6) were associated, without toxicity, ILS % values of 50 and 58, respectively. Combining gemcitabine and PNU 166196 at the same doses with the same schedule, an increase of activity with ILS % values of 127 were observed, thus indicating a synergistic effect.
TABLE 1
Antileukemic activity against disseminated L12101 murine leukemia
of an acryloyl distamycin derivative (I)
in combination with gemcitabine.
Treatment Dose2
Compound schedule (mg/kg/day) ILS %3 Tox4
PNU 166196 iv + 1.6 0.78 58 0/10
Gemcitabine iv + 1 (*) 15 50 0/10
PNU 166196 + iv + 1.6 0.78+ 127 0/10
Gemcitabine iv + 1 15
1L1210 leukemia cells (105/mouse) are injected iv on day 0.
2Treatment is given starting on day 1 after tumor transplantation (day 0).
3Increase in life span: [(median survival time of treated mice/median survival time of controls) × 100] − 100
4Number of toxic deaths/number of mice.
(*) treatment 2 h after PNU 166196 administration.

Claims (9)

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and, as active ingredient, an acryloyl distamycin derivative of formula (I):
Figure US07642229-20100105-C00006
wherein:
R1 is a bromine or chlorine atom;
R2 is a group of formula (II)
Figure US07642229-20100105-C00007
wherein
m is an integer from 0 to 2;
n is an integer from 2 to 5;
r is 0 or 1;
X and Y are the same or different and are independently, for each heterocyclic ring, a nitrogen atom or a CH group;
G is phenylene, a 5 or 6 membered saturated or unsaturated heterocyclic ring with from 1 to 3 heteroatoms selected from the group consisting of N, O and S, or a group of formula III
Figure US07642229-20100105-C00008
whererin Q is a nitrogen atom or a CH group; and W is an oxygen or sulfur atom or an NR3 group, wherein R3 is a hydrogen or C1-C4 alkyl;
B is selected from the group consisting of
Figure US07642229-20100105-C00009
—CN; —NR5R6; —CONR5R6; —NHCONR5R6
wherein R4 is cyano, amino, hydroxyl or C1-C4 alkoxy; R5, R6 and R7 are the same or different and are hydrogen or C1-C4 alkyl; or a pharmaceutically acceptable salt thereof and an antimicrotubule agent, wherein the antimicrotubule agent is docetaxel.
2. The pharmaceutical composition according to claim 1 wherein r is 0, m is 0 or 1, and n is 4.
3. The pharmaceutical composition according to claim 2 wherein X and Y are both CH groups and B is selected from the group consisting of:
Figure US07642229-20100105-C00010
—CH; —CONR5R6; and —NHCONR5R6,
wherein R1 is cyano or hydroxy and R5, R5 and R7 are the same or different and are hydrogen or C1-C4 alkyl.
4. The pharmaceutical composition according to claim 1 wherein said acryloyl distamycin derivative, optionally in the form of a pharmaceutically acceptable salt, is selected from the group consisting of:
(1) N(5-{[(5-{[(5-{[(2-{[amino(imino)methyl]amino }ethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbon- yl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1methyl-1H-pyrrole-2-carboxamide hydrochloride;
(2) N(5-{[(5-{[(5-{[(2-{[amino(imino)methyl]amino }propyl)amino]carbonyl}-1-methyl-1H-pyrrol-3yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride;
(3) N-5-{[(5-{[(5-{[(3-amino-3-iminopropyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride;
(4) N-(5-{[(5-{[(5-{[(3-amino-3-iminopropyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-imidazole-2-carboxamide hydrochloride;
(5) N-(5-{[(5-{[(5-{[(3-amino-3-iminopropyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-3-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrazole-5-carboxamide hydrochloride;
(6) N-(5-{[(5-{[(5-{[(3-amino-3-oxopropyl)amino]carbonyl}- 1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-3-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrazole-5-carboxamide;
(7) N-(5-{[(5-{[(5-{[(2-{[amino(imino)methyl]amino }ethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-chloroacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride;
(8) N-(5-{[(5-{[(3-{[amino(imino)methyl]am1- amino}propyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride;
(9) N-5-{[(5-{[(3-amino-3-iminopropyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromo-acryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride; and
(10) N-{5-[({5-[({5-[({3-[(aminocarbonyl)amino]propyl}amino)carbonyl]-1-methyl-1H-pyrrol-3-yl}amino)carbonyl]-1-methyl-1H-pyrrol-3-yl}amino)carbonyl]-1-methyl-1H-pyrrol-3-yl}-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyyrole-2-carboxamide.
5. The pharmaceutical composition according to claim 1 wherein said acryloyl distamycin derivative of formula (I) is PNU 166196.
6. A method of treating a mammal suffering from a neoplastic disease state, comprising administering to said mammal an acryloyl distamycin derivative of formula (I):
Figure US07642229-20100105-C00011
wherein:
R1 is a bromine or chlorine atom;
R2 is a group of formula (II)
Figure US07642229-20100105-C00012
wherein
m is an integer from 0 to 2;
n is an integer from 2 to 5;
r is 0 or 1;
X and Y are the same or different and are independently, for each heterocyclic ring, a nitrogen atom or a CH group;
G is phenylene, a 5 or 6 membered saturated or unsaturated heterocyclic ring with from 1 to 3 heteroatoms selected from the group consisting of N, O and S, or a group of formula III
Figure US07642229-20100105-C00013
whererin Q is a nitrogen atom or a CH group; and W is an oxygen or sulfur atom or an NR3 group, wherein R3 is a hydrogen or C1-C4 alkyl;
B is selected from the group consisting of
Figure US07642229-20100105-C00014
—CN; —NR5R6; —CONR5R6; —NHCONR5R6
wherein R4 is cyano, amino, hydroxyl or C1-C4 alkoxy; R5, R6 and R7 are the same or different and are hydrogen or C1-C4 alkyl; or a pharmaceutically acceptable salt thereof;
and an antimicrotubule agent, wherein the antimicrotubule agent is docetaxel, in amounts effective to produce a synergistic antineoplastic effect, wherein the neoplastic disease state is selected from the group consisting of breast, ovary, lung, colon, kidney, stomach, pancreas, liver, melanoma, leukemia and brain tumors.
7. The method according to claim 6 wherein the acryloyl distamycin derivative is selected from the group consisting of:
(1) N(5-{[(5-{[(5-{[(2-{[amino(imino)methyl]amino }ethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbon- yl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1methyl-1H-pyrrole-2-carboxamide hydrochloride;
(2) N(5-{[(5-{[(5-{[(2-{[amino(imino)methyl]amino }propyl)amino]carbonyl}-1-methyl-1H-pyrrol-3yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride;
(3) N-5-{[(5-{[(5-{[(3-amino-3-iminopropyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride;
(4) N-(5-{[(5-{[(5-{[(3-amino-3-iminopropyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}- 1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-imidazole-2-carboxamide hydrochloride;
(5) N-(5-{[(5-{[(5-{[(3-amino-3-iminopropyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-3-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrazole-5-carboxamide hydrochloride;
(6) N-(5 -{[(5-{[(5-{[(3-amino-3-oxopropyl)amino]carbonyl}- 1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}- 1-methyl-1H-pyrrol-3-yl)-3-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrazole-5-carboxamide;
(7) N-(5-{[(5-{[(5-{[(2-{[amino(imino)methyl]amino }ethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1methyl-1H-pyrrol-3-yl)amino]carbonyl}- 1-methyl-1H-pyrrol-3-yl)-4-[(2-chloroacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride;
(8) N-(5-{[(5-{[(3-{[amino(imino)methyl]amino}propyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride;
(9) N-5-{[(5-{[(3-amino-3-iminopropyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromo-acryloyl)amino]- 1-methyl-1H-pyrrole-2-carboxamide hydrochloride; and
(10) N-{5-[({5-[({5-[({3-[(aminocarbonyl)amino]propyl}amino)carbonyl]-1-methyl-1H-pyrrol-3-yl}amino)carbonyl]-1-methyl-1H-pyrrol-3-yl}amino)carbonyl]-1-methyl-1H-pyrrol-3-yl}-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyyrole-2-carboxamide.
8. A method for lowering the side effects caused by antineoplastic therapy with an antineoplastic agent, in a mammal in need thereof, comprising administering to said mammal a combined preparation comprising an acryloyl distamycin derivative of formula (I):
Figure US07642229-20100105-C00015
wherein:
R1 is a bromine or chlorine atom;
R2 is a group of formula (II)
Figure US07642229-20100105-C00016
wherein
m is an integer from 0 to 2;
n is an integer from 2 to 5;
r is 0 or 1;
X and Y are the same or different and are independently, for each heterocyclic ring, a nitrogen atom or a CH group;
G is phenylene, a 5 or 6 membered saturated or unsaturated heterocyclic ring with from 1 to 3 heteroatoms selected from the group consisting of N, O and S, or a group of formula III
Figure US07642229-20100105-C00017
whererin Q is a nitrogen atom or a CH group; and W is an oxygen or sulfur atom or an NR3 group, wherein R3 is a hydrogen or C1-C4 alkyl;
B is selected from the group consisting of
Figure US07642229-20100105-C00018
—CN; —NR5R6; —CONR5R6; —NHCONR5R6
wherein R4 is cyano, amino, hydroxyl or C1-C4 alkoxy; R5, R6 and R7 are the same or different and are hydrogen or C1-C4 alkyl; or a pharmaceutically acceptable salt thereof;
and an antimicrotubule agent, wherein the antimicrotubule agent is docetaxel, in amounts effective to produce a synergistic antineoplastic effect.
9. The method according to claim 6 or 8, wherein the mammal is a human.
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